Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inflammatory process in rheumatoid arthritis provokes intense bone resorption, evidenced as bone erosions, juxta-articular osteopenia and generalized osteoporosis. These types of bone loss share a common pathogenesis, and the role of osteoclasts in focal bone erosion was verified in elegant animal studies. The tumour necrosis factor (TNF) family of cytokines and receptors--specifically TNF-alpha, RANKL, RANK and OPG--are dominant regulators of osteoclastic bone resorption in rheumatoid arthritis. The confirmation of the osteoclast mechanism provides new insight into the structural joint protection afforded by disease-modifying drugs and suggests innovative approaches to limit bone destruction. Emerging treatment strategies for bone disease in rheumatoid arthritis are the use of monoclonal antibodies to neutralize RANKL, and powerful bisphosphonates that target pathogenic osteoclasts.
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PMID:Bone loss in inflammatory arthritis: mechanisms and therapeutic approaches with bisphosphonates. 1630 Nov 97

Hundreds of millions of people worldwide are affected by bone-related diseases, such as osteoporosis and rheumatoid arthritis. Understanding the molecular mechanisms of bone metabolism is crucial for developing novel drugs for treating such diseases. In particular, genetic experiments showing that the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor OPG are essential, central regulators of osteoclast development and osteoclast function were significant turning points in our understanding of bone diseases. RANKL-RANK signaling activates a variety of downstream signaling pathways required for osteoclast development. Moreover, molecular cross-talk between RANKL-RANK and other ligand-receptor systems fine-tunes bone homeostasis in normal physiology and disease. Designing novel drugs that target RANKL-RANK and their signaling pathways in osteoclasts could potentially revolutionize the treatment of many diseases associated with bone loss such as arthritis, tooth loss, cancer metastases or osteoporosis.
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PMID:RANKL-RANK signaling in osteoclastogenesis and bone disease. 1635 70

Osteoporosis and associated fractures are the most common and debilitating complication of glucocorticoid use. The use of alternative anti-inflammatory agents without the deleterious skeletal effects of glucocorticoids is needed. Dehydroepiandrosterone (DHEA) may have immunomodulatory as well as positive effects on bone. For our further understanding of the mechanisms of action of DHEA, as a steroid-sparing agent, we investigated and compared the effects of dexamethasone (DEX) and DHEA on the regulation of the downstream effector pathway of osteoclastogenesis; RANKL/OPG and a range of inflammatory/pro-resorbing cytokines and receptors using a human clonal osteoblastic cell line. The cells were treated with DEX, DHEA, and androstenedione (ANDI). The mRNA expression of RANKL and OPG was determined by real-time PCR after overnight incubation. The regulation of a broad spectrum of cytokines by DEX and DHEA was also investigated using a human cytokine/growth factor and receptor gene array consisting of 268 cytokine-related cDNAs. To confirm some of the gene expression changes, protein production was measured by ELISA. RANKL expression and RANKL/OPG ratio were increased by DEX. This effect was reversed by co-treatment with both DHEA or ANDI. Several pro-inflammatory/resorptive cytokines including IL-6, IL-4, IFN-gamma, macrophage inhibitory factor (MIF) were down-regulated not only by DEX but also by DHEA. In contrast to DEX, DHEA did not lead to suppression of growth factors including vascular endothelial growth factor (VEGF), fibroblast growth factor-5 (FGF-5), insulin-like growth factor-binding protein3 (IGF-BP3). Several new target genes previously documented to influence bone formation were up-regulated by DHEA such as Notch 2, insulin receptor, thrombin receptor (PAR1). The data suggest that DHEA has immunomodulatory properties without the catabolic effects on bone remodeling, observed with glucocorticoid use. DHEA may thus prove useful as a steroid-sparing agent in the management of inflammatory disorders such as SLE or rheumatoid arthritis. Further in vivo studies are indicated.
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PMID:The effects of dexamethasone and dehydroepiandrosterone (DHEA) on cytokines and receptor expression in a human osteoblastic cell line: potential steroid-sparing role for DHEA. 1716 16

Inflammatory bone loss is observed in a number of disorders including rheumatoid arthritis (RA), osteoporosis and periodontal disease. Lymphocytes are key components in the onset and exacerbation of autoimmune diseases and the cytokines produced by these cells have a powerful impact on disease progression. Many cytokines implicated in inflammation impact upon osteoclast (OCL) differentiation and function either directly or indirectly by modulating the relative expression of RANKL and OPG. This review highlights the contribution of lymphocyte-derived cytokines to the bone loss observed in RA and other autoimmune disorders. A greater understanding of the cytokines involved in these disorders will ultimately lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases.
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PMID:Lymphocyte-derived cytokines in inflammatory arthritis. 1836 37

Molecular signals of RANK/RANK/OPG, essentially required in osteoclast differentiation, have been shown to pertain to joint destruction in rheumatoid arthritis (RA) . In rodent adjuvant arthritis systemic administration of OPG did not prevent inflammation, but effectively reduced joint destruction preserving peri-arthritic bone mass. In clinical trial anti-RANKL antibody (Denosumab) injection once in every 6 months alleviated the worsening of joint erosion in hands for a year in patients with RA. Although RANKL/RANK signals have not been confirmed as the exclusive causative factor to joint destruction and bone loss, a new horizon may be brought about by Denosumab in the treatment of RA.
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PMID:[Expectation for alleviation of joint destruction in rheumatoid arthritis by new molecular targeting pharmaceutics including anti-rankle antibody]. 1925 48

We should consider not only controlling disease activity using DMARDs and biologics as a matter of course, but also preventing against joint destruction, in the treatment for rheumatoid arthritis. Although we can indirectly regulate bone erosion via controlling disease activity, the osteoclast-targeting therapy might be more effective to stop joint destruction. We are waiting for new drugs directly targeting osteoclasts, such as OPG which is the natural inhibitor of RANKL, or cathepsin K inhibitor which reduces degeneration of bone matrix.
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PMID:[Prevention of joint destruction by osteoclast-targeting therapy in search of new tools, such as OPG or cathepsin K inhibitor]. 1925 49

The TNF family members RANKL and its receptor RANK have initially been described as factors expressed on T cells and dendritic cells (DCs), respectively, and have been shown to augment the ability of DCs to stimulate naive T cell proliferation and enhance DC survival. Since another, yet soluble receptor for RANKL, namely OPG, was initially characterized as a factor inhibiting osteoclast development and bone resorption, it was somewhat enigmatic at first why one and the same genes would be essential both for the immune system and bone development - two processes that on first sight do not have much in common. However, in a series of experiments it was conclusively shown that RANKL-expressing T cells can also activate RANK-expressing osteoclasts, and thereby in principal mimicking RANKL-expressing osteoblasts. These findings lead to a paradigm shift and helped to coin the term osteoimmunology in order to account for the crosstalk of immune cells and bone. More importantly was that these findings also provided a rationale for the bone loss observed in patients with a chronically activated immune system such as in rheumatoid arthritis, leukemias, or the like, arguing that T cells, which were activated during the course of the disease to fight it off, also express RANKL, which induces osteoclastogenesis and thereby shifts the intricate balance of bone deposition and resorption in favor of the latter. Through knockout mice it became also clear that the RANKL-RANK-OPG system is involved in other processes such as in controlling autoimmunity or immune responses in the skin. We will briefly summarize the role of RANK(L) signaling in the immune system before we discuss some of the recent data we and others have obtained on the role of RANK(L) in controlling autoimmunity and immune responses in the skin.
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PMID:Novel functions of RANK(L) signaling in the immune system. 1995 18

Our previous study showed that Leukotriene B4 can directly stimulate osteoclast differentiation independent of RANKL. In order to determine whether Leukotriene B4 could indirectly stimulate human osteoclast differentiation through increasing RANKL expression of rheumatoid arthritis fibroblast-like synoviocytes, we utilize the coculture model of rheumatoid arthritis fibroblast-like synoviocytes and monocyte, which were stimulated in the presence of 2.5 ng/ml M-CSF in the control group, 2.5 ng/ml M-CSF+10(-8)M LTB4 in the experimental group a, and 2.5 ng/ml M-CSF+10(-8)M LTB4+100 ng/ml OPG in the experimental group b. After culture for 3 weeks, the number of multinucleated TRAP staining positive osteoclast-like cells stained with TRAP was counted to evaluate the differentiation effect in each group. There was almost no osteoclast-like cell in the control group and the experimental group b. There were many osteoclast-like cells in the experimental group a. These results indicated that Leukotriene B4 is capable of inducing osteoclast differentiation by a RANKL-dependent mechanism.
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PMID:LTB4 can stimulate human osteoclast differentiation dependent of RANKL. 2004 21

Osteoclasts, bone-resorbing multinucleated cells, are differentiated from hemopoietic progenitors of the monocyte/macrophage lineage. Bone resorption by osteoclasts is considered a potential therapeutic target to the treatment of erosive bone diseases, including osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we found that alisol-B, a phyto-steroid from Alisma orientale Juzepczuk, exhibited inhibitory effects on osteoclastogenesis both in vitro and in vivo. Although RT-PCR analysis showed that alisol-B did not affect the 1alpha,25(OH)(2)D(3)-induced expressions of RANKL, OPG and M-CSF mRNAs in osteoblasts, addition of alisol-B to co-cultures of mouse bone marrow cells and primary osteoblasts with 10(-8)M 1alpha,25(OH)(2)D(3) caused significant inhibition of osteoclastogenesis. We further examined the direct effects of alisol-B on osteoclast precursors. Alisol-B strongly inhibited RANKL-induced osteoclast formation when added during the early stage of cultures, suggesting that alisol-B acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, alisol-B inhibited the phosphorylation of JNK, which are upregulated in response to RANKL in bone marrow macrophages, alisol-B also inhibited RANKL-induced expression of NFATc1 and c-Fos, which are key transcription factors for osteoclastogenesis. In addition, alisol-B suppressed the pit-forming activity and disrupted the actin ring formation of mature osteoclasts. In a hypercalcemic mouse model induced by 2-methylene-19-nor-(20S)-1alpha,25(OH)(2)D(3) (2MD), an analog of 1alpha,25(OH)(2)D(3), administration of alisol-B significantly suppressed 2MD-induced hypercalcemia as resulting from the inhibition of osteoclastogenesis. Taken together, these findings suggest that alisol-B may be a potential novel therapeutic molecule for bone disorders by targeting the differentiation of osteoclasts as well as their functions.
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PMID:Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice. 2041 88

Vasoactive intestinal peptide (VIP) is a well-known anti-inflammatory neuropeptide. The capacity of VIP can be exhibited through inhibiting inflammatory responses, shifting the Th1/Th2 balance in favor of anti-inflammatory Th2 immunity and inducing regulatory T cells (Tregs) with suppressive activity. In addition to pro-inflammatory Th1 response, Th17 are also believed to play important roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we used collagen-induced arthritis (CIA) model in Wistar rats to investigate the role of VIP in the balance of CD4(+) CD25(+) Tregs and Th17 on RA. Data presented here showed that administration of VIP decreased incidence and severity of CIA. Disease suppression was associated with the upregulation of CD4(+) CD25(+) Tregs, downregulation of Th17- and Th1-type response and influence on the RANK/RANKL/OPG system. The results provide novel evidence that the therapeutic effects of VIP on CIA rats were associated with the balance of CD4(+) CD25(+) Tregs and Th17.
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PMID:Regulatory effect of vasoactive intestinal peptide on the balance of Treg and Th17 in collagen-induced arthritis. 2071 49


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